Molecular insights into the modulation of the 5HT2A receptor by serotonin, psilocin, and the G protein subunit Gqα.
FEBS letters March 1, 2025 Niklas Viohl, Ali Asghar Hakami Zanjani, Himanshu Khandelia 7 citations
The 5HT2AR receptor, a G-protein-coupled receptor targeted by psychedelic drugs, collapses to a closed active state without Gqα, revealing an intermediate partially-open conformation. Molecular dynamics simulations and free-energy calculations show that serotonin and psilocin bind more tightly to the orthosteric pocket than to the extended binding pocket. These findings clarify activation mechanisms and may guide development of novel therapeutics for neurological and psychiatric disorders.